P342	Molecular mechanisms regulating the mobilization of neutrophils from the bone marrow.
S.Rankin, C.Martin, P.Burdon
Imperial College, NHLI Division, Leukocyte Biology Section, SAF building, Exhibition Rd, South Kensington, London, GB.

During an inflammatory reaction neutrophils are released from the bone marrow reserve. This acute mobilization is stimulated by systemically acting inflammatory mediators, such as the CXC chemokines. We propose that mature neutrophils reside in the haematopoietic cords of the bone marrow and migrate across the sinuoidal endothelium in response to a rise in the chemokine concentration in the bone marrow sinusoids. In this study we have examined this mobilization by transmission and scanning electron microscopy and shown that migration occurs via a transcellular pathway. We have used an in situ perfusion system of the rat femural bone marrow to investigate the molecular mechanisms regulating this mobilization process. Using this sytem we have shown that infusion of the CXC chemokine rat MIP-2 into the femoral artery stimulates a rapid, dose dependent mobilization of neutrophils into the femoral vein. Using specific blocking mAbs we have investigated the role of CD18 and CD29 intergins in this process and shown that CD18 intergins are not required for the chemokine-stimulated mobilization of neutrophils while unexpectedly CD49d (VLA4) is critical for this process. While previous studies have suggested a role for MMPs in mobilization in this system we show that the activity of MMPs is not required for neutrophil mobilization. P38 MAP kinase has been reported to play a role in neutrophil chemotaxis in vitro and in vivo. We show here that an inhibitor of p38 MAPkinase inhibits the chemotaxis of rat bone marrow neutrophils in vitro and mobilization in situ.

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